Kimura A, Nishiyori A, Murakami T, Tsukamoto T, Hata S, Osumi T, Okamura R, Mori M, Takiguchi M
Department of Molecular Genetics, Kumamoto University School of Medicine, Japan.
J Biol Chem. 1993 May 25;268(15):11125-33.
Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4) are orphan members of the steroid/thyroid receptor superfamily and exhibit ubiquitous and liver-enriched tissue distribution, respectively. The gene for rat ornithine transcarbamylase (OTC), an ornithine cycle enzyme, is mainly expressed in the liver and is under the control of the promoter and the 11-kilobase upstream enhancer, both of which are liver-selective. Two sites of the promoter region and two sites of the enhancer region of the OTC gene, as well as the ovalbumin promoter site, were recognized by both HNF-4 and COUP-TF, showing that these two factors have closely related binding specificities. Since HNF-4 activated expression from the OTC promoter in cotransfection analysis, this factor appears to participate in liver-selective activation of the OTC gene. On the other hand, COUP-TF repressed the expression from the OTC promoter, whereas it activated expression from several other promoters. Therefore, COUP-TF plays a dual regulatory role depending on the promoter context. Repression of a tissue-specific promoter by a ubiquitous transactivator and derepression by a related tissue-enriched transactivator is potentially an important mechanism for tissue-specific activation of a gene.
鸡卵清蛋白上游启动子转录因子（COUP-TF）和肝细胞核因子-4（HNF-4）是类固醇/甲状腺受体超家族的孤儿成员，分别呈现广泛分布和肝脏富集的组织分布。大鼠鸟氨酸转氨甲酰酶（OTC）是一种鸟氨酸循环酶，其基因主要在肝脏中表达，并受启动子和11千碱基上游增强子的调控，这两者均具有肝脏选择性。OTC基因启动子区域的两个位点、增强子区域的两个位点以及卵清蛋白启动子位点均可被HNF-4和COUP-TF识别，表明这两个因子具有密切相关的结合特异性。由于在共转染分析中HNF-4激活了OTC启动子的表达，该因子似乎参与了OTC基因的肝脏选择性激活。另一方面，COUP-TF抑制了OTC启动子的表达，而激活了其他几个启动子的表达。因此，COUP-TF根据启动子环境发挥双重调节作用。一种广泛存在的反式激活因子对组织特异性启动子的抑制以及一种相关的组织富集反式激活因子对其的去抑制作用可能是基因组织特异性激活的重要机制。
